U.S. patent application number 11/313706 was filed with the patent office on 2006-07-06 for regimens for intra-articular viscosupplementation.
This patent application is currently assigned to Genzyme Corporation. Invention is credited to Francois Bailleul.
Application Number | 20060148755 11/313706 |
Document ID | / |
Family ID | 36633154 |
Filed Date | 2006-07-06 |
United States Patent
Application |
20060148755 |
Kind Code |
A1 |
Bailleul; Francois |
July 6, 2006 |
Regimens for intra-articular viscosupplementation
Abstract
The invention provides viscosupplementation methods for treating
osteoarthritis and joint injury with HA-based viscosupplements,
particularly viscosupplements with an intra-articular residence
half-life shorter than 3 weeks. Viscosupplements for use in the
methods of the invention may be further characterized in that they
contain less than 20 mg/ml HA, at least 5% (w/w) of which is in a
gel form, such as, e.g., hylan B. In an illustrative embodiment,
hylan G-F 20 (Synvisc.RTM.) is administered in a single
intra-articular knee injection of 6.+-.2 ml.
Inventors: |
Bailleul; Francois; (Paris,
FR) |
Correspondence
Address: |
GENZYME CORPORATION;LEGAL DEPARTMENT
15 PLEASANT ST CONNECTOR
FRAMINGHAM
MA
01701-9322
US
|
Assignee: |
Genzyme Corporation
Cambridge
MA
|
Family ID: |
36633154 |
Appl. No.: |
11/313706 |
Filed: |
December 20, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60640749 |
Dec 30, 2004 |
|
|
|
Current U.S.
Class: |
514/54 |
Current CPC
Class: |
A61P 5/44 20180101; A61P
19/00 20180101; A61P 19/02 20180101; A61K 9/0024 20130101; A61P
25/04 20180101; A61P 29/00 20180101; A61P 19/08 20180101; A61K
31/728 20130101; A61P 25/00 20180101; A61P 35/00 20180101; A61P
23/00 20180101; A61P 31/12 20180101 |
Class at
Publication: |
514/054 |
International
Class: |
A61K 31/728 20060101
A61K031/728 |
Claims
1. A viscosupplementation method for treating a knee joint of a
subject, the method consisting of a single intra-articular
administration of 4 ml or more.
2. The method of claim 1, wherein the viscosupplement contains less
than 20 mg/ml HA.
3. The method of claim 1, wherein the subject is human.
4. The method of claim 3, wherein the total volume of the
viscosupplement in the single administration is 6.+-.2 ml or
more.
5. The method of claim 4, wherein the amount is 6 ml.
6. The method of claim 1, wherein the viscosupplement is
administered to a subject in need of treatment of joint pain.
7. The method of claim 1, wherein the single administration of the
viscosupplement is therapeutically effective for at least 4
months.
8. The method of claim 1, wherein the viscosupplement is
characterized by one or more features as follows: (i) the
viscosupplement has a residence half-life of less than 3 weeks;
(ii) the viscosupplement contains less than 20 mg/ml HA; (iii) 5%
(w/w) or more of HA in the viscosupplement is in a gel form.
9. The method of claim 8, wherein the residence half-life is more
than 3 days.
10. The method of claim 1, wherein the viscosupplement contains
8.+-.2 mg/ml HA.
11. The method of claim 1, wherein the HA in the viscosupplement is
of animal origin.
12. The method of claim 11, wherein the viscosupplement is produced
from rooster combs.
13. The method of claim 1, wherein the HA in the viscosupplement is
of bacterial origin.
14. The method of claim 1, wherein at least a fraction of the
viscosupplement has been crosslinked.
15. The method of claim 14, wherein the crosslinker is
formaldehyde.
16. The method of claim 15, wherein the viscosupplement comprises
hylan A.
17. The method of claim 16, wherein an average molecular weight of
HA in hylan A is 6,000 kDa.
18. The method of claim 14, wherein the crosslinker is divinyl
sulfone.
19. The method of claim 18, wherein the viscosupplement comprises
hylan B.
20. The method of claim 14, wherein the viscosupplement comprises
hylan A and hylan B.
21. The method of claim 20, wherein the hylan A/hylan B ratio is
9:1 by weight of HA.
22. The method of claim 1, wherein the viscosupplement contains
8.+-.2 mg/ml HA, of which 10% by weight is in a gel form.
23. The method of claim 1, wherein the viscosupplement is
Synvisc.RTM..
24. The method of claim 23, wherein the viscosupplement further
comprises a component selected from the group consisting of
non-steroidal anti-inflammatory drug, anaesthetic, opioid
analgesics, corticosteroids, antineoplastic agent, and anti-viral
agent.
25. A viscosupplementation method for treating a knee joint of a
human subject, the method consisting of a single intra-articular
administration of 6.+-.2 ml Synvisc.RTM..
26. The method of claim 25, wherein the amount administered is 6
ml.
27. A method of treating a joint pathology comprising the
viscosupplementation method of claim 1.
28. The method of claim 27, wherein the joint pathology is
associated with osteoarthritis.
29. A method of treating osteoarthritic pain in a knee joint of a
human subject, the method comprising administering a single
intra-articular injection of 6.+-.2 ml Synvisc.RTM..
30. The method of claim 31, wherein the amount is 6 ml.
31. A viscosupplementation device, comprising a syringe containing
4 ml or more of Synvisc.RTM..
32. The device of claim 31, which is sterile.
33. The device of claim 31, wherein the syringe contains 6.+-.2 ml
of Synvisc.RTM..
34. The device of claim 31, wherein the amount of Synvisc.RTM. in
the syringe is 6 ml.
35. The device of claim 31, wherein Synvisc.RTM. further comprises
a component selected from the group consisting of non-steroidal
anti-inflammatory drug, anesthetic, opioid analgesics,
corticosteroids, antineoplastic agent, anti-viral agent, and cells.
Description
FIELD OF THE INVENTION
[0001] This invention relates to rheumatology and orthopaedics.
More specifically, the invention relates to treatment of cartilage
pathology (e.g., osteoarthritis) by viscosupplementation.
BACKGROUND OF THE INVENTION
[0002] Osteoarthritis (OA) is a progressive degenerative disorder
characterized by a breakdown of the cartilage in the joints, a
deterioration of the synovial fluid present in the articular
joints, and a subchondral osteosclerosis accompanied by osteophyte
formation. Patients with OA often exhibit severe pain that affects
many aspects of their daily living. The prevalence of OA increases
with age, with more than 60% of those 60 years old or older likely
to have some cartilage abnormality (Bjelle (1982) Scand. J.
Rheumatol. Suppl., 43:35-48). OA has become the most costly form of
arthritis, collectively accounting for up to 1-2.5% of the gross
national product of Western nations (Reginster (2002) Rheumatology,
41 (Suppl. 1):3-6).
[0003] Synovial fluid lubricates and protects the intra-articular
joint surfaces. The fluid is primarily composed of high molecular
weight polysaccharide hyaluronan (HA, sodium salt of hyaluronic
acid, also known as sodium hyaluronate). The concentration of HA in
the normal human synovial joint fluid is approximately 3 mg/ml. HA
consists of repeating disaccharide units of N-acetylglucosamine and
sodium glucuronate (FIG. 1). HA in the normal synovial fluid of the
joints contains 12,500 disaccharide units with total molecular
weight (MW) of 5 MDa (Balazs et al. (1993) J. Rheumatol. Suppl.,
39:3-9). In OA patients, the concentration and MW of HA in synovial
fluid decreases, resulting in the diminished capacity of the fluid
to protect the cartilage.
[0004] Intra-articular injection of an elastoviscous solution
containing high molecular weight HA has been shown to restore the
normal homeostasis of the diseased joint. This procedure, known as
viscosupplementation, has proven effective in reducing pain and
enhancing joint function (see, e.g., Balazs et al. (1993) J.
Rheumatol. Suppl., 39:3-9; Wobig (1998) Clin. Ther.,
20(3):410-423).
[0005] A number of HA-based viscosupplements are available on the
market and new products are being developed. Viscosupplements vary
in a number of characteristics including, for example, the source
of HA (animal-derived or bacterial), the concentration and MW of
HA, and the type and degree of chemical crosslinking used, if any.
Usually, most viscosupplements contain 5-15 mg/ml HA and, once
injected, have residence half-life between hours to several days.
Such viscosupplements are injected into the knee in 2-3 ml unit
volumes in a series of three to five injections each one week
apart. In some cases, pain relief occurs within a few days,
continues to progress over a few weeks, and often lasts for several
months, even up to a year. For example, knee viscosupplementation
with Synvisc.RTM. (hylan G-F 20; Genzyme Corp., Cambridge, Mass.)
administered three times at 2 ml weekly has been demonstrated to be
at least as good, or better, than continuous oral therapy with
non-steroidal anti-inflammatory drugs (NSAIDs) plus arthrocentesis
over a period of 6 months (Adams et al. (1995) Osteoarthritis and
Cartilage, 3:213-225) and more effective than a saline placebo or
arthrocentesis controls (Moreland (1993) Am. Coll. Rheumatol. (57th
Ann. Sci. Meeting, Nov. 7-11, San Antonio, Tex.), 165; Wobig (1998)
Clin. Ther., 20(3):410-423).
[0006] The series of multiple injections have been thought to be
essential for a prolonged (six months to one year) effect on
osteoarthritic pain primarily because of the short residence
half-life of most viscosupplements (Peyron (1993) J. Rheumatol.,
20(Suppl. 39):10-15). For example, an intra-articular residence
half-life of 1% HA with an average MW of 1.7-2.6 MDa is 11 hours,
as determined in rabbits. As MW of HA increases, so does the
residence half-life (e.g., 1% hylan A, in which the average MW of
HA is 6 MDa, has a half-life of 1.2.+-.1 day). However, even an
insoluble gel, such as hylan B containing 0.4% HA, has a relatively
short residence half-life of 7.7.+-.1 days. Consistent with the
half-life data, three 2 ml injections of Synvisc.RTM. into an OA
knee were demonstrated to be significantly more effective for
reducing OA pain than two 2 ml injections (Scale et al. (1994)
Curr. Ther. Res., 55(3):220-232).
[0007] For treatment with Synvisc.RTM. of patients with OA of the
hip, the recommended dose is one 2 ml injection with a second
optional injection administered between one and three months if
insufficient pain relief is experienced (Chevalier (2000) Am. Coll.
Rheumatol. (64th Annual Scientific Meeting, Oct. 30-Nov. 3,
Philadelphia, Pa.)). In hip OA patients, a single intra-articular
injection of Synvisc.RTM. at 2 ml showed a significant immediate
and sustained symptomatic effect in the majority of enrolled
patients for up to three months (duration of the study). It has not
been investigated whether greater volumes of viscosupplements, such
as Synvisc.RTM. (e.g., 4, 6 ml or greater), could offer equivalent
or better efficacy with fewer injections compared to multiple
injection of 2-3 ml, or a single injection of 2 ml. As far as was
known, the use of larger volumes potentially posed a risk of local
adverse effects such as pain, swelling, and effusion.
[0008] Durolane.TM. (Q-Med AB, Uppsala, Sweden) is the only
viscosupplement that is recommended to be injected once, at 3 ml.
It is an epoxy-crosslinked viscosupplement with a longer reported
half-life (4 weeks) and a higher concentration of HA (20 mg/ml).
The prolonged residence time is thought to allow the reduced number
of injections. Nevertheless, a single injection of Durolane.TM. did
not demonstrate statistical benefits over placebo (Altman et al.
(2004) Osteoarthritis and Cart., 12:642-649).
[0009] Thus, prior to the present invention, it was not known
whether a single injection of an HA-based viscosupplement,
particularly one with a short residence life, can produce a desired
long-term therapeutic effect.
[0010] The use of fewer injections offers apparent advantages over
the multiple injections, including avoidance of adverse effects,
reduced costs, and better patient compliance. A continued need
exists to develop new viscosupplementation treatments that provide
effective relief to OA patients without necessitating multiple
injections.
SUMMARY OF THE INVENTION
[0011] The invention provides methods and compositions for treating
joint pathology, and for reducing pain and discomfort associated
with such pathology. Examples of such pathology include
osteoarthritis and joint injury.
[0012] The invention is based, at least in part, on the discovery
that a single intra-articular injection of a greater volume of a
viscosupplement provides long-term therapeutic benefits comparable
to those produced by serial injections of smaller volumes. In a
study conducted in connection with the invention, one group of knee
OA patients received the standard sequence of three 2 ml injections
of Synvisc.RTM. in the knee over a three-week period, while another
group received a single injection of 6 ml under identical
conditions. Surprisingly, therapeutic efficacy, as evaluated at 26
weeks following the treatment, was found to be comparable in both
groups. Thus, a single injection of a greater volume of a
viscosupplement, such as Synvisc.RTM., can be as effective as
several injections of smaller volumes, while maintaining a
favorable safety profile.
[0013] Accordingly, the invention provides regimens for
intra-articular viscosupplementation with HA-based
viscosupplements, particularly viscosupplements with
intra-articular residence half-life (T.sub.1/2) shorter than 3
weeks. Viscosupplements for use in the methods of the invention may
be further characterized in that they contain less than 20 mg/ml HA
(derivatized and/or nonderivatized), at least 5% of which is in a
gel form such as, e.g., hylan B. In an illustrative embodiment, the
viscosupplement is hylan G-F 20 (Synvisc.RTM.), which contains
8.+-.2 mg/ml HA, of which 10% by weight is in a gel form.
[0014] In some embodiments, a viscosupplement is administered in a
single injection in an amount sufficient to provide a therapeutic
effect for up to 6 months following the injection. In some
embodiments, the therapeutic effect of a single injection of a
larger volume is substantially the same as that achieved by three
injections (each 1/3 of the larger volume) administered over a
course of treatment. In an illustrative embodiment, Synvisc.RTM. is
administered in a single injection of 6 ml, rather than three 2 ml
injections, over a three-week period.
[0015] Methods of administration, compositions and devices used in
the methods of the invention are also provided.
[0016] The foregoing summary and the following description are not
restrictive of the invention as claimed.
BRIEF DESCRIPTION OF THE FIGURES
[0017] FIG. 1 illustrates the structure of hyaluronan (sodium
hyaluronate).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0018] The terms "intra-articular half-life," "residence
half-life," and their cognates refer to the time which is the
greater of any of the times applicable to a given viscosupplement
injected into the intra-articular space: (a) the time required for
clearance of 50% of the HA gel component injected; (b) the time
required for clearance of 50% of the HA fluid component injected;
and (c) the time required for clearance of 50% of HA, regardless
whether it is fluid, gel, or another form. For the purposes of
residence half-life calculation, unless stated otherwise, the
injection is considered to be administered into the intra-articular
space of a knee joint of an adult human. Methods for determining
residence half-life are known in the art and illustrative methods
are described in the Examples.
[0019] The terms "HA fluid," "HA fluid phase," "HA fluid
component," "soluble HA," and their cognates refer to uncrosslinked
or lightly crosslinked water-soluble HA with an average MW of less
than 20 MDa.
[0020] The term "HA gel," "HA gel phase," "HA gel component," and
their cognates refer to HA gel which is a water-insoluble part of
an HA-based composition that does not contain soluble HA or
contains less than 10% (w/w) of soluble HA. Typically, the amount
of gel in a given HA-based composition containing a mix of HA gel
and HA fluid can be determined by separating HA gel from HA fluid.
The separation can be accomplished by filtering the composition
through, e.g., a 45 p filter, which passes through soluble HA yet
retains the insoluble phase. In order to maximize the release of
soluble HA from the HA gel in more viscous compositions, a
composition may need to be diluted with several volume of a solvent
with or without bringing it to the equilibrium prior to filtration.
Furthermore, generally, pure gels can be distinguished from pure
fluids based on their rheological properties, such as storage
(elastic) modulus (G') and loss (viscous) modulus (G''), which
represent respectively the relative degrees a material can recover
(elastic response) or flow (viscous response) as the rate of
deformation (test frequency) changes. Both moduli are linear
functions of the frequency. They have proven to be sensitive probes
of the structure of polymer solutions and gels. Both G' and G''
increase with increasing frequency, but one increases more quickly
than the other. At the point where G'=G'', this frequency is called
cross-over frequency (f.sub.c). The cross-over frequency decreases
with increasing polymer molecular weight or concentration. For a
polymer solution at low frequency, elastic stresses relax and
viscous stresses dominate, and as a result G'' is greater than G'
at frequencies below f.sub.c. In contrast, for a gel, there is no
cross-over between G' and G'', and G' is greater than G'' across
the frequency range. Unless otherwise specified, the test frequency
is 0.04-7 Hz. For a review of physical properties of viscoelastic
materials and methods of measuring these properties, see, e.g.,
"Polymers as Rheology Modifiers", edited by Schulz and Glass, ACS
Symposium Series 462, 1991; "An Introduction to Rheology," H. A.
Barnes, J. F. Hutton and K. Walters, Elsevier, 1989; and Bohlin
Rheometer Application Notes MRK544-01, MRK556-01, and
MRK573-01.
[0021] The terms "HA," "hyaluronate," "hyaluronan" are used
interchangeably, and unless stated otherwise, refer to any HA,
regardless of the source (bacterially fermented or animal-derived),
molecular weight, its physical form (e.g., gel or fluid), or the
presence or absence of chemical modifications (e.g., crosslinked or
otherwise derivatized), or method of production.
Regimens
[0022] The invention provides viscosupplementation methods and
related methods. According to the invention, viscosupplementation
methods consist of administering a single intra-articular injection
of viscosupplement within a period of 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 weeks,
in the amount sufficient to provide a therapeutic effect for up to
4, 5, or 6 months following the injection. In some embodiments, the
therapeutic effect of a single injection of a larger volume is
substantially the same as that achieved by three injections (each
1/3 of the larger volume) administered over a course of treatment.
In some embodiments, the single injection regimen provides reduced
joint pain for up to 4, 5, or 6 months following the injection.
[0023] The therapeutic effect can be assessed by any suitable
method (see, e.g., Altman et al. (1996) Osteoarth. Cart.,
4:217-243). For example, the therapeutic effect may be assessed by
measuring a reduction in joint pain. The degree of joint pain can
be classified according to a five-point Likert scale (e.g., none,
mild, moderate, severe, very severe) or on a 100 mm visual analog
scale (VAS) as described in the Examples. Other suitable pain
indices include the Health Assessment Questionnaire (HAQ) (Fries et
al. (1980) Arthritis Rheumatol., 23:137-145) and Arthritis Impact
Measurement Scale (AIMS) (Meenan et al. (1980) Arthritis
Rheumatol., 23:146-154.
[0024] The therapeutic effect may also be assessed by measuring the
improvement in the degree of functional impairment. Functional
impairment can be measured by using a segregated, validated
multidimensional index (SMI) such as the Western Ontario and
McMaster's Universities (WOMAC.TM.) OA index for hip and knee OA
(Bellamy et al. (1988) J. Rheumatol. 34:1833-1840; see, also,
Examples); or an aggregated multidimensional index (AMI) such as
the Algo-Functional Index (AFI) for hip or knee (Lequesne et al.
(1987) Scand. J. Rheumatol. Suppl., 65:85-89).
[0025] The therapeutic effect may also be evaluated by global
status assessment by a patient or a physician. Global status can be
assessed using a Likert or VAS scale, e.g., as described in the
Examples.
[0026] Additional indicia of therapeutic effect may include joint
examination (see, e.g., Theiler et al. (1994) Osteoarth. Cart.,
2:1-24), performance based measures (see, e.g., Rejeski et al.
(1995) Osteoarth. Cart., 3:157-168), etc.
[0027] In some embodiments, a viscosupplement is administered into
the knee joint in the amount of 6.+-.2 ml or more, e.g., 4, 4.25,
4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5,
7.75, 8 ml or more.
Viscosupplements
[0028] An HA-based viscosupplement useful in the methods of the
invention is characterized by any one, any two, or all of the
features as follows:
[0029] (i) the viscosupplement has a residence half-life of less
than 3 weeks;
[0030] (ii) the viscosupplement contains less than 20 mg/ml HA;
[0031] (iii) 5% (w/w) or more of HA in the viscosupplement is in a
gel form.
[0032] In an illustrative embodiment, the viscosupplement used in
the methods of the invention is Synvisc.RTM.. Synvisc.RTM. contains
8.+-.2 mg/ml HA in two forms: a soluble form, hylan A, (average MW
6,000 kDa) and a hydrated gel form, hylan B, in a physiologically
acceptable solution. The hylan A/hylan B ratio in Synvisc.RTM. is
9:1 by weight of HA. Hylan A is a water-soluble hyaluronan
chemically modified by covalent crosslinking with small amounts of
an aldehyde, typically formaldehyde, while hylan B is hylan A
further crosslinked by divinyl sulfone. Hylan fluid is hydrated
hylan A, a modified form of hyaluronan with a small number of
crosslinks which increase its average molecular weight and augment
its elastoviscous properties. Hylan gel is the hydrated form of
hylan B, and is prepared by crosslinking hylan A into a continuous
polymeric network, using divinyl sulfone as a bifunctional
crosslinking reagent.
[0033] Generally, viscosupplements used in the regimens provided by
the invention include HA-based viscosupplements having
intra-articular residence half-life shorter than 22 days, e.g., 21,
20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, and 3
days. In some embodiments, residence half-life of the
viscosupplement is more than 2, 3, 4, 5, 6, or 7 days.
[0034] Viscosupplements used in the methods of the invention may be
further characterized in that they contain less than 20 mg/ml HA,
e.g., in the range of 1-15, 1-10, 1-5, 5-15, 5-10, 10-15, 6-10, and
7-9 mg/ml. The amount of HA in a given composition can be
determined by any suitable methods as described, e.g., in the
Examples.
[0035] Viscosupplement compositions used in the methods of the
invention may be further characterized in that at least 10% by
weight of HA in the viscosupplement is in a gel form. For example,
in some embodiments, the viscosupplement comprises at least 5%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%,
80%, 85%, 90%, 95%, 99% or more HA gel. In some embodiments, the
viscosupplement contains 10-90%, 10-75%, 10-50%, 10-40%, 10-25% HA
gel. In some embodiments, the ratio of HA gel/HA fluid in the
viscosupplement contains ranges from 1:50-10:1 (w/w), e.g., 1:50,
1:25, 1:15, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2; 1:1, 2:1,
3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1.
[0036] Viscosupplements for use in the methods of the invention may
further contain water-soluble HA in a fluid phase, with MW of HA in
the range of 500-20,000 kDa, e.g., 500-1,000,500-1,500; 500-3,000;
500-5,000; 500-7,000; 500-10,000; 500-15,000; 1,000-1,500;
1,000-3,000; 1,000-5,000; 1,000-7,000; 1,000-10,000; 1,000-15,000;
5,000-10,000; and 10,000-15,000 kDa.
[0037] HA may be of animal origin, e.g., derived from rooster combs
or umbilical cords, or non-animal origin, e.g., bacterially
fermented. Bacterially fermented HA can be produced as described
in, e.g., Cooney et al. (1999) Biotechnol. Prog., 15:898-910.
Bacterially fermented HA is also available commercially (e.g.,
Shiseido, Japan; Sigma-Aldrich, USA).
[0038] HA may be derivatized (e.g., crosslinked or otherwise
modified or stabilized) or nonderivatized. Examples of crosslinkers
include aldehyde, epoxide, polyaziril, glycidyl ether (e.g.,
1,4-butandiol diglycidylether), and divinyl sulfone.
[0039] Specific examples of viscosupplements useful in the methods
of inventions include Adant.TM., Arthrease.TM., Arthrum.TM.,
Fermathron.TM., Go-on.TM., Hyalart.TM./Hyalgan.TM., Hy-GAG.TM.,
Hya-ject.TM., Hyalubrix.TM., NeoVisc.TM., Supartz.TM./Artz.TM.,
Synvisc.RTM., Orthovisc.TM., Ostenil.TM., Sinovial.TM.,
Suplasyn.TM., and Synochrom.TM., Viscorneal.TM. (see, e.g.,
Physicians' Desk Reference.TM., 2004). Other products suitable in
the methods of the invention include viscosupplements described in
U.S. Pat. Nos. 5,143,724; 4,713,448; 5,099,013; 5,399,351;
6,521,223; 5,827,937; U.S. Patent Application No. 60/533,429.
[0040] Preparation of hylans and viscosupplements including
linoleum hylan A and hylan B is described in, e.g., U.S. Pat. Nos.
5,143,724; 4,713,448; 5,099,013; and 5,399,351.
[0041] In some embodiments, the viscosupplements exclude
Durolane.TM. and/or other viscosupplements with a residence
half-life of longer than 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,
48, 49, or 50 days.
[0042] Viscosupplements may also contain additional active or
inactive components including, for example, the non-steroidal
anti-inflammatory drugs (NSAIDs), e.g., lbuprofen.TM.,
Diclofenac.TM., and Piroxicam.TM.; anaesthetics, e.g.,
Lidocaine.TM. and Bupivacaine.TM.; opioid analgesics, e.g., codeine
and morphine; corticosteroids, e.g., dexamethasone and prednisone;
antineoplastic agents such a Methotrexate.TM., 5-fluorouracil and
Paclitaxel.TM.; and anti-viral agents, e.g., Acyclovir.TM. and
Vidarabine.TM.. Viscosupplements may also contain components such
as cells (e.g., chondrocytes or mesenchimal stem cells), proteins,
DNA, vitamins or other desirable biologically active material.
Uses and Administration
[0043] The invention provides methods and composition for treating
subjects with joint pathology and for reducing pain and discomfort
associated with such pathology. Examples of such pathology include
osteoarthritis (primary (idiopathic) or secondary), rheumatoid
arthritis, joint injury (e.g., repetitive motion injury), cartilage
pathology (chondromalacia), and pre-arthritic states. The invention
further provides methods of reducing pain associated with such
pathologies. The methods can be practiced in humans in need of
treatment for joint pathology or in nonhuman subjects.
[0044] Examples of administration sites include the knee, shoulder,
temporo-mandibular and carpo-metacarpal joints, elbow, hip, wrist,
ankle, and lumbar zygapophysial (facet) joints in the spine. The
volumes injected into any of these joints would be at least double
of the currently recommended dose for that joint.
[0045] The invention further provides a viscosupplementation device
comprising a pre-filled, single-use syringe having a single unit
dosage of 6.+-.2 ml Synvisc.RTM., e.g., 4, 4.25, 4.5, 4.75, 5,
5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25,
8.5, 8.75, 9, 9.25, 9.5, 9.75, 10 ml or more. Although it is
preferred to provide the single administration dose with a use of a
single syringe provided here, the required dose may be provided
with two or more syringes. For example, a single administration of
6 ml may be accomplished using 3 syringes containing 2 ml each.
[0046] The following Examples provide illustrative embodiments. The
Examples do not in any way limit the invention. One of ordinary
skill in the art will recognize numerous modifications and
variations that may be performed within the scope of the present
invention. Such modifications and variations are therefore
encompassed by the invention.
EXAMPLES
Example 1
Intra-Articular Injection of Synvisc.RTM. in Patients with OA
[0047] A prospective, open-label study was conducted to evaluate
the safety and efficacy (including duration of action) of
intra-articular injections of 4 ml or 6 ml of Synvisc.RTM. against
the current dosing regimen of three intra-articular injections of 2
ml Synvisc.RTM. in ambulatory patients with symptomatic
tibio-femoral OA (global OA pain in the study knee in the range of
50-80 on a 100 mm VAS score). Other criteria for inclusion were:
age of 40 years or older; Kellgren-Lawrence grade II-III by X-ray
within 3 last months; absence of tense effusion, mechanical
deficit, or recent (<2 years) trauma. 100 patients (mean age 61
years ranging from 59 to 66, 55% females) were randomized in five
groups:
[0048] Group 1--one injection of 6 ml;
[0049] Group 2--one injection of 4 ml;
[0050] Group 3--two injections of 4 ml two weeks apart;
[0051] Group 4--three 4 ml injections one week apart; and
[0052] Group 5--the standard regimen of three 2 ml injections one
week apart.
[0053] The patients were then followed up to 6 months (at weeks 2,
3, 8, 16, and 24). The primary and secondary assessment endpoints
used are described below.
[0054] A. Patient Self-assessment of OA Pain
[0055] The primary efficacy endpoint of this study is to evaluate
the efficacy of visco-supplementation with Synvisc.RTM. in patients
with OA of the knee with respect to study knee OA pain relief. This
is measured on a patient self assessed 100-mm VAS, with endpoints
of no pain (0 mm) to extreme pain (100 mm) within the past 48
hours; performed at 24 weeks following the first injection.
[0056] B. Patient Global Self-Assessment
[0057] The patient rated the overall status of their target knee on
the 100-mm VAS which ranged from very good (0 mm) to very poor (100
mm), taking into account all related signs and symptoms over the
previous 48 hours. The exact instructions presented to the patient
were the following: "Please indicate by using a vertical line
below, the overall general condition of your (study) knee at the
time of this visit. The left or `0` score indicates `Very good`
while the `100` score indicates `Very poor`."
[0058] C. WOMACT.TM.
[0059] The patient completed the VAS version of the WOMAC.TM. as
described in Bellamy et al. (1988) J. Rheumatol., 15(12):1833-40.
This scale is a tri-dimensional, disease-specific,
self-administered, health status measure. It probes clinically
important, patient-relevant symptoms in the areas of pain,
stiffness and physical function in a total of 24 questions. The
WOMAC.TM. was provided to the patient in the local language and was
usually completed in less than 5 minutes. The WOMAC.TM.
sub-sections are the following.
[0060] The WOMAC.TM. Section A consists of questions regarding
levels of pain during activity and the responses are scored (by the
patient) with a VAS that ranges from no pain (0 mm) to extreme pain
(100 mm). Assessment of pain is made for the following scenarios:
TABLE-US-00001 1. Walking on a flat surface? [walking] 2. Going up
or down stairs? [stair climbing] 3. At night while lying in bed?
[nocturnal] 4. Sitting or lying? [rest] 5. Standing upright?
[weight bearing]
The mean sub-score for the WOMAC Section A was based on the
responses to each of the components of Section A.
[0061] The WOMAC.TM. Part B (Stiffness Score) consists of questions
regarding stiffness severity during activity and the responses are
scored (by the patient) with a VAS that ranges from no stiffness (0
mm) to extreme stiffness (100 mm). Assessment of stiffness was made
for the following scenarios: TABLE-US-00002 1. After waking in the
morning? [morning stiffness] 2. During rest later in the day?
[stiffness occurring later in the day]
The mean sub-score for Section B was based on the responses to each
of the components of Section B.
[0062] The WOMAC.TM. Section C consists of questions regarding
functional impairment during activity and the responses are scored
(by the patient) with a VAS that ranges from no difficulty (Q mm)
to extreme difficulty (100 mm). Assessment of functional impairment
was made for the following scenarios: TABLE-US-00003 1. Descending
stairs? [morning stiffness] 2. Ascending stairs? [stiffness
occurring later in the day] 3. Rising from sitting? [rising
sitting] 4. Standing? [standing] 5. Bending to the floor? [bending]
6. Walking on flat surfaces? [flat walking] 7. Getting in and out
of car? [car] 8. Going shopping? [shopping] 9. Putting on
socks/stockings [socks/stockings off] 10. Lying in bed [lying in
bed] 11. Getting in/out of bath [in/out bath] 12. Sitting [sitting]
13. Getting on/off toilet [on/off toilet] 14. Heavy domestic duties
[heavy domestic] 15. Light domestic duties [light domestic]
The mean sub-score for Section C was based on the responses to each
of the components of Section C.
[0063] The change from baseline in the total WOMAC.TM. score
derived from the 3 WOMAC.TM. sections (A, B and C) at all time
points following the first injection was analyzed as a secondary
endpoint.
[0064] D. Physician OA Global Assessment
[0065] After the patient has completed the global assessments and
the WOMAC.TM., the Investigator rated the overall condition of the
patient's knee at the time of the visit on the 100-mm VAS ranging
from very good (0 mm) to very poor (100 mm). This evaluation was
based on the patient's signs of disease, functional capacity and
physical examination. The physician was instructed to indicate the
overall general condition of the patient's knee at the time of this
visit, using a line presented with the left ("0") extreme of the
line indicating "very good" and the right extreme ("100")
indicating "very poor."
[0066] E. Results
[0067] The results showing reduction of pain (VAS; 0 corresponding
to no pain and 100 to extreme pain, within the past 48 hours) at 24
weeks following the first injection as compared to baseline is
shown in Table 1. Pain dropped by 34.9 mm in the 1.times.6 ml group
as compared with 36.7 mm in the 3.times.2 ml group which scored the
best. In the groups treated by 1.times.4 or 2.times.4 ml, this
decrease was less dramatic (only 24 mm reduction). TABLE-US-00004
TABLE 1 Patient self-assessment of OA pain (change from baseline)
Group 1 2 3 4 5 1 .times. 6 ml 1 .times. 4 ml 2 .times. 4 ml 3
.times. 4 ml 3 .times. 2 ml Mean -34.9 -24.3 -24.0 -32.6 -36.7 Std.
Dev. 16.4 28.3 22.9 25.3 26.9 95% Cl -42.5, -37.2, -35.0, -44.4,
-49.2, -27.2 -11.5 -13.0 -20.8 -24.1
[0068] Secondary efficacy endpoints including improvement in pain,
stiffness and functional impairment as measured by the Western
Ontario and McMaster Universities Osteoarthritis Index (WOMAC.TM.)
(Table 2 for WOMAC.TM. A), patient (Table 3) and physician (Table
4) global knee OA assessments, showed the same trends. Treatment
groups were ranked in order of efficacy and the results are shown
in Table 5. The prolonged duration of the effect observed in group
1 was surprising. In terms of safety, 10% of the patients in each
group (1.times.6 ml and 3.times.2 ml) reported related local knee
adverse events (pain, swelling or effusion) of minimal or moderate
intensity. TABLE-US-00005 TABLE 2 WOMAC .TM. A pain score (change
from baseline) Group 1 2 3 4 5 1 .times. 6 ml 1 .times. 4 ml 2
.times. 4 ml 3 .times. 4 ml 3 .times. 2 ml Mean -25.8 -14.7 -16.6
-27.7 -25.6 Std. Dev. 22.5 24.2 24.8 27.2 24.6 95% Cl -36.3, -25.7,
-28.5, -40.5, -37.1, -15.3 -3.7 -4.6 -14.9 -14.1
[0069] TABLE-US-00006 TABLE 3 Patient global assessment (change
from baseline) Group 1 2 3 4 5 1 .times. 6 ml 1 .times. 4 ml 2
.times. 4 ml 3 .times. 4 ml 3 .times. 2 ml Mean -31.3 -14.3 -19.8
-25.9 -24.4 Std. Dev. 26 31 24 32.9 32.3 95% Cl -43.4, -28.4,
-31.2, -41.3, -39.5, -19.1 -0.2 -8.2 -10.5 -9.3
[0070] TABLE-US-00007 TABLE 4 Physician global assessment (change
from baseline) Group 1 2 3 4 5 1 .times. 6 ml 1 .times. 4 ml 2
.times. 4 ml 3 .times. 4 ml 3 .times. 2 ml Mean -30.7 -16.8 -22.9
-25.9 -27.7 Std. Dev. 18.3 24.8 26.9 25.0 29.6 95% Cl -39.5, -28.1,
-35.8, -37.5, -41.6, -21.9 -5.5 -10.0 -14.2 -13.8
[0071] TABLE-US-00008 TABLE 5 Treatment group rankings Group 1 2 3
4 5 1 .times. 6 ml 1 .times. 4 ml 2 .times. 4 ml 3 .times. 4 ml 3
.times. 2 ml Pt. pain 2 4 5 3 1 Pt. global 1 5 4 2 3 Phy. global 1
5 4 3 2 WOMAC .TM. 2 5 4 1 3 A WOMAC .TM. 4 5 3 2 1 B WOMAC .TM. 2
4 5 1 3 C
[0072] No large differences were observed between the treatment
groups with respect to safety, only that Group 1 (1.times.6 ml) had
in general the least adverse effects. These results also suggest
that volumes of Synvisc.RTM. larger than 2 ml can be safely
administered to reduce pain in patients with osteoarthritis of the
knee.
Example 2
Determination of Synvisc.RTM. Residence Half-Life
[0073] A. Incorporation of .sup.14C-Acetate into the Hyaluronan of
Rooster Comb Organ Cultures
[0074] Young roosters (3-6 months of age) were sacrificed by
cervical dislocation. Their combs were thoroughly cleansed with
(80%) ethanol, and then excised at the base using a scalpel. Excess
blood was pressed out of the comb, and it was placed into sterile
saline solution, transferred to a laminar flow hood, and rinsed in
three additional volumes of sterile saline solution. The comb was
then dissected along the vascular midline, and rectangular segments
of pink dermal tissue were excised. The comb tissue segments were
thinly sliced with a scalpel and placed into Ventrex media HL-1
(Ventrex Labs), 5 mg/ml testosterone propionate (Belmar
Laboratories, Inwood, N.Y.), 20 .mu.Ci/ml of .sup.14C-acetic acid
(ICN Radiochemicals, Irvine, Calif., 1 mCi/ml), 0.1 mg/ml
penicillin, 0.1 mg/ml streptomycin and 0.1 mg/ml fungizone
(Hazelton, Lenexa, Kans.). Individual cultures were done in 60 mm
plastic Petri dishes and contained approximately 1.5 g of comb
tissue and 15 ml of the media. The cultures were incubated for 72
hours in a 5% CO.sub.2 environment, after which the tissue was
separated from the media by centrifugation for 10 minutes at 10,000
g. The tissue pellet was frozen in a 30 mm Petri dish. The frozen
radiolabeled comb tissue was typically kept in the freezer for 1-72
hours prior to continued processing to prepare hylan.
[0075] B. Preparation of Radiolabeled Hylan Fluid
[0076] Hylan A fibers were prepared as follows. Slices of frozen
radiolabeled comb tissue were placed into a reaction medium
containing acetone, formalin (37% formaldehyde solution),
chloroform, and sodium acetate at a ratio of 0.75 g tissue per 1 g
of reaction medium. The reaction was allowed to proceed for 18-20
hours, after which the tissue slices were harvested, washed three
times in acetone, and then dried in a laminar flow hood. Four
volumes of distilled water were then added to the dry tissue slices
in order to extract radiolabeled hylan. This aqueous extraction was
performed at 4-6.degree. C., after which the aqueous extract was
removed, and an identical volume of water was added back for a
second extraction. Solid sodium acetate was dissolved into the
aqueous extracts to a concentration of 1%, and hylan fibers were
precipitated by the slow addition into four volumes of 95% ethanol.
The radiolabeled hylan fibers were washed twice in acetone, and
stored in the cold under acetone.
[0077] Radiolabeled hylan A fibers (40.3 mg) were pooled and
dissolved into 3.0 ml of sterile, pyrogen-free, phosphate buffered
saline solution (Biotrics Inc., Ridgefield, N.J., lot 122-1) by
slow end-over-end mixing for 3 days at 4.degree. C. After complete
dissolution, the radioactive hylan fluid was diluted five-fold with
non-labeled hylan fluid. The mixture was kept for an additional
five days on the end-over-end mixture at 4.degree. C.
[0078] C. Preparation of Radiolabeled Gel
[0079] Tritiated water (New England Nuclear, 100 mCi/ml) was mixed
into the reaction mixture used to crosslink hylan fluid (hylan A)
into hylan gel (hylan B). The crosslinking reaction was run as
follows. Hylan A fibers were allowed to swell in the tritiated
water for approximately three hours. Concentrated sodium hydroxide
was added and the mixture was vigorously stirred until the solution
was homogeneous (approximately 15 minutes). Divinyl sulfone was
diluted to a concentration of 50% in water, and added into the
reaction mixture with vigorous stirring. The reaction mixture was
allowed to stand at room temperature (22.degree. C.) for an
additional 55 minutes during which the polysaccharide chains were
crosslinked by divinyl sulfone into a continuous polymeric gel
(hylan gel). By performing this reaction in tritiated water,
tritium becomes covalently attached to carbon within the divinyl
sulfonyl crosslink. The reaction was terminated by the addition of
ten volumes of sterile pyrogen-free saline solution to lower the pH
below 12. Saline washing also results in a swelling of the hylan
gel to its equilibrium hydration. The hylan gel was washed with
saline to remove unreacted divinyl sulfone, unreacted tritium, and
other reaction products, and to bring the pH down to 7. Excess
saline was separated from the gel by filtration, after which the
gel was passed through a 25 g needle 5 times to break up the solid
gel into an easily injectable form. In this form, the tritiated gel
was exhaustively dialyzed against sterile, pyrogen-free saline to
remove any non-covalently bound tritium.
[0080] D. Preparation of a Hylan Gel-Hylan Fluid Mixture
[0081] Tritiated hylan gel (3.04 g) was directly added into 11.63 g
of .sup.14C-hylan fluid, and the mixture was placed on a Glen Mills
mixer for 48 hours. The mixture was then passed ten times through
18 g, 21 g, and 25 g needles successively to assure homogeneity and
ease of injection.
[0082] E. Measurements of HA Concentration and Radiolabel
Amounts
[0083] The concentration of hylan polysaccharide in the gel and
fluid components of the mixture were determined by the automated
carbazole procedure for assaying its repeating glucuronic acid
monomer (3) and multiplying by (2.07) to account for the remainder
of the polysaccharide chain. Hylan gel was hydrolyzed prior to
glucuronic acid determination by adding weighed 0.1 g samples of
the gel to 0.2 ml of 1N H.sub.2SO.sub.4 in tightly capped screw top
tubes, and allowing acid hydrolysis to proceed for 2 hours at
100.degree. C. The samples, which were completely solubilized by
this procedure, were neutralized with 0.2 ml of 1N NaOH prior to
analyzing HA by a carbazole procedure.
[0084] The carbazole procedure involves measuring the amount of
hexuronic acid (glucuronic acid) in the sample. A method for
determining hexuronic acid concentration by a colorimetric method
was reported by Dische et al. (1947) J. Biol. Chem., 167:189-198.
The method is based on the color reaction of hexuronic acids with
sulfuric acid and carbazole. An updated, automated method for the
determination of hexuronic acids was reported by Balazs et al.
(1965) Anal. Biochem., 12:547-558. The samples are heated in a
sulfuric acid/borate medium and reacted with carbazole. The
carbazole reacts with the hexuronic acid to form a pink complex
with an absorbance maximum at 530 nm. For the automated method, the
samples and standards are aspirated through a continuous flow
analyzer using a peristaltic pump. The reagents (acid and
carbazole) are added and heated in a reaction chamber, the
absorbance is read by a continuous flow colorimeter at 530 nm.
[0085] Radioactivity content of the test article was determined by
scintillation counting in an ISOCAP 300 liquid scintillation
counter (Nuclear Chicago) using Scintiverse Bio HP (Fisher
Scientific) as a scintillant. Raw CPM data was converted to DPM
using the ISOCAP 300's external standards ratio program, with
standardization against Tritium Liquid Scintillation Quench
Standards, or Carbon-14 Liquid Scintillation Quench Standards
(Amergham, Arlington Heights, Ill.).
[0086] F. Determination of Synvisc.RTM. Residence Half-Life
[0087] The clearance of Synvisc.RTM. and its gel and fluid
components from the knee joint were determined in New Zealand White
rabbits weighing between 2.5 and 3.5 kg. Rabbit were sacrificed at
24 hours, 3, 7, and 28 days, respectively. The radioactive material
prepared essentially as described above was administered as an
intra-articular injection of 0.3 ml (0.086 ml/kg body weight). This
dose level is expected to be equivalent to a single 6 ml
administration of Synvisc.RTM. to a 70 kg human. Corresponding
amounts to be administered in other animals are likewise directly
proportional to the weight of the animal.
[0088] DPMs were obtained for each tissue as outlined above, and
DPM/mg was calculated directly when appropriate. The total DPMs
recovered and both DPMs and DPM/mg for each joint tissue were
calculated separately for each animal. These values were then
averaged for each time point and, expressed as mean.+-.the standard
error of the mean. Calculated averages were reported to a minimum
of two significant digits, even in situations where the values were
small and the animal to animal variation was large. Total average
DPM recovered from the joint at each time point was calculated by
averaging the individual animal totals.
[0089] Half-life determinations were made by fitting the means for
each time to an exponential function (Y=Ae.sup.kx). The standard
error of the estimate was obtained from the curve fit and divided
by A to obtain the expected percent error. This was multiplied by
the half-life to obtain the expected error of the half-life.
[0090] G. Results
[0091] The gel component (hylan B) of Synvisc.RTM. is the longer
half-life moiety. Based on the clearance of the radioactive
material, the gel component's residence half-life was determined to
be 7.7-8.8 days. Thus, by day 30, more than 95% of the gel would be
cleared. Theoretical calculations, based on the experimentally
determined half-life of the gel, were conducted to estimate the
amount of gel expected to be in the human joint following a single
6 ml injection. Assuming that approximately 6 mg of gel was
injected into the knee of a human subject, at 21 days following the
injection the amount of gel remaining would be approximately 0.9
mg.
[0092] The fluid component of Synvisc.RTM. (hylan A) clears more
rapidly than the gel component. The half-life of the fluid
component was determined to be 1.2-1.5 days. By 7 days, 99% of the
injected material was cleared from the rabbit knee joint.
[0093] Rabbit muscle implant studies were also conducted.
Microscopic examination at 7 and 30 days post-implantation did not
detect any residual test material, which is consistent with the
intra-articular clearance studies.
[0094] The specification is most thoroughly understood in light of
the teachings of the references cited within the specification. The
embodiments within the specification provide an illustration of
embodiments of the invention and should not be construed to limit
the scope of the invention. The skilled artisan readily recognizes
that many other embodiments are encompassed by the invention. All
publications and patents cited in this disclosure are incorporated
by reference in their entirety. To the extent the material
incorporated by reference contradicts or is inconsistent with the
present specification, the present specification will supersede any
such material. The citation of any references herein is not an
admission that such references are prior art to the present
invention.
[0095] Unless otherwise indicated, all numbers expressing
quantities of ingredients, cell culture and treatment conditions,
and so forth used in the specification, including claims, are to be
understood as being modified in all instances by the term "about."
Accordingly, unless otherwise indicated to the contrary, the
numerical parameters are approximations and may vary depending upon
the desired properties sought to be obtained by the present
invention. Unless otherwise indicated, the term "at least"
preceding a series of elements is to be understood to refer to
every element in the series. Those skilled in the art will
recognize, or be able to ascertain using no more than routine
experimentation, many equivalents to the specific embodiments of
the invention described herein. Such equivalents are intended to be
encompassed by the following claims.
* * * * *